We recently identified a novel link between hypoxia, which is a hallmark of human malignancies, and cancer cell metabolism. We showed that hypoxia dramatically induces a previously under-appreciated metabolic pathway in cancer cells, namely the generation of cytosolic Acetyl-Coa (AcCoA) by reductive carboxylation of cytosolic ?-ketoglutarate (?KG) to isocitrate. Our preliminary data indicate that Isocitrate Dehydrogenase 1, an enzyme mutated in gliomas and acute leukemias, is necessary for this phenomenon and that the transcription factors Hypoxia Inducible Factors (HIFs) and the hypoxia-regulated cytosolic enzyme Aco1 are likely implicated in mediating this hypoxia effect. Our work highlights that hypoxia-induced metabolic changes of cancer cells present an opportunity for development of therapies targeting a broad range of human malignancies. In this application we propose to dissect the molecular mechanism(s) mediating the hypoxia-induced reductive carboxylation by and to validate critical enzymes of reductive carboxylation as therapeutic targets for tumor suppression in vivo. PUBLIC HEALTH RELEVANCE: Cancer cells have a metabolism which differs from the metabolism of normal cells. In addition, almost all cancers learn how to grow in hypoxic environments. We discovered a new mechanism that links hypoxia and cancer cell metabolism and we propose experiments that will highlight the molecular mechanisms of this link and will identify critical proteins that can target this mechanism for anti-cancer therapy. This is an underappreciated area of work that opens new opportunities for cancer therapy.